Amine and amide derivatives as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders

ABSTRACT

Amine and amide derivatives of the formula:  
                 
which are ligands for the neuropeptide Y Y5 (NPY5) receptor, methods of preparation and pharmaceutical compositions containing amines and amides of formula A as the active ingredient are described. The amines and amides of formula A are useful in the treatment of disorders and diseases associated with NPY receptor subtype Y5.

FIELD OF THE INVENTION

This invention relates to a series of amine and amide derivatives,pharmaceutical compositions containing them and intermediates used intheir preparation. The compounds of the invention are ligands for theneuropeptide Y Y5 (NPY5) receptor, a receptor which is associated with anumber of central nervous system disorders and affective conditions. Inaddition, many of the compounds of the invention reduce food consumptionin a rodent model of feeding.

BACKGROUND OF THE INVENTION

Regulation and function of the mammalian central nervous system isgoverned by a series of interdependent receptors, neurons,neurotransmitters, and proteins. The neurons play a vital role in thissystem, for when externally or internally stimulated, they react byreleasing neurotransmitters that bind to specific proteins. Commonexamples of endogenous small molecule neurotransmitters such asacetylcholine, adrenaline, norepinephrine, dopamine, serotonin,glutamate, and gamma-aminobutyric acid are well known, as are thespecific receptors that recognize these compounds as ligands (“TheBiochemical Basis of Neuropharmacology”, Sixth Edition, Cooper, J. R.;Bloom, F. E.; Roth, R. H. Eds., Oxford University Press, New York, N.Y.1991).

In addition to the endogenous small molecule neurotransmitters, there isincreasing evidence that neuropeptides play an integral role in neuronaloperations. Neuropeptides are now believed to be co-localized withperhaps more than one-half of the 100 billion neurons of the humancentral nervous system. In addition to humans, neuropeptides have beendiscovered in a number of animal species. In some instances thecomposition of these peptides is remarkably homogenous among species.This finding suggests that the function of neuropeptides is vital andhas been impervious to evolutionary changes. Furthermore, neuropeptides,unlike small molecule neurotransmitters, are typically synthesized bythe neuronal ribosome. In some cases, the active neuropeptides areproduced as part of a larger protein which is enzymatically processed toyield the active substance. Based upon these differences, compared tosmall molecule neurotransmitters, neuropeptide-based strategies mayoffer novel therapies for CNS diseases and disorders. Specifically,agents that affect the binding of neuropeptides to their respectivereceptors or ameliorate responses that are mediated by neuropeptides arepotential therapies for diseases associated with neuropeptides.

There are a number of afflictions that are associated with the complexinterdependent system of receptors and ligands within the centralnervous system; these include neurodegenerative diseases, affectivedisorders such as anxiety, depression, pain and schizophrenia, andaffective conditions that include a metabolic component, namely obesity.Such conditions, disorders and diseases have been treated with smallmolecules and peptides which modulate neuronal responses to endogenousneurotransmitters.

One example of the class of neuropeptides is neuropeptide Y (NPY). NPYwas first isolated from porcine brain (Tatemoto, K. et al. Nature 1982,296, 659) and was shown to be structurally similar to other members ofthe pancreatic polypeptide (PP) family such as peptide YY, which isprimarily synthesized by endocrine cells in the gut, and pancreaticpolypeptide, which is synthesized by the pancreas. Neuropeptide Y is asingle peptide protein that consists of thirty-six amino acidscontaining an amidated C-terminus. Like other members of the pancreaticpolypeptide family, NPY has a distinctive conformation that consists ofan N-terminal polyproline helical region and an amphiphilic α-helixjoined by a characteristic PP-fold (Vladimir, S. et. Al. Biochemistry1990, 20, 4509). Furthermore, NPY sequences from a number of animalspecies have been elucidated and all show a high degree of amino acidhomology to the human protein (>94% in rat, dog, rabbit, pig, cow,sheep) (see Larhammar, D. in “The Biology of Neuropeptide Y and RelatedPeptides”, Colmers, W. F. and Wahlestedt, C. Eds., Humana Press, Totowa,N.J. 1993).

Endogenous receptor proteins that bind NPY and related peptides asligands have been identified and distinguished, and several suchproteins have been cloned and expressed. Six different receptor subtypes[Y1, Y2, Y3, Y4(PP), Y5, Y6 (formerly designated as a Y5 receptor)] arerecognized today based upon binding profile, pharmacology and/orcomposition if identity is known (Wahlestedt, C. et. al. Ann. NY Acad.Sci. 1990, 611, 7; Larhammar, D. et. al. J. Biol. Chem. 1992, 267,10935; Wahlestedt, C. et. al. Regul. Pept. 1986, 13, 307; Fuhlendorff,J. U. et. al. Proc. Natl. Acad. Sci. USA 1990, 87, 182; Grundemar, L.et. al. J. Pharmacol. Exp. Ther. 1991, 258, 633; Laburthe, M. et. al.Endocrinology 1986, 118, 1910; Castan, I. et. al. Endocrinology 1992,131, 1970; Gerald, C. et. al. Nature 1996, 382, 168; Weinberg, D. H. et.al. Journal of Biological Chemistry 1996, 271, 16435; Gehlert, D. et.al. Current Pharmaceutical Design 1995, 1, 295; Lundberg, J. M. et. al.Trends in Pharmaceutical Sciences 1996, 17, 301). Most and perhaps allNPY receptor proteins belong to the family of so-called G-proteincoupled receptors (GPCRs). The neuropeptide Y5 receptor, a putativeGPCR, is negatively coupled to cellular cyclic adenosine monophosphate(cAMP) levels via the action of adenylate cyclase (Gerald, C. et. al.Nature 1996, 382, 168; Gerald, C. et. al. PCT WO 96/16542). For example,NPY inhibits forskolin-stimulated cAMP production/levels in aneuroblastoma cell line. A Y5 ligand that mimics NPY in this fashion isan agonist whereas one that competitively reverses the NPY inhibition offorskolin-stimulated cAMP production is an antagonist.

Neuropeptide Y itself is the archetypal substrate for the NPY receptorsand its binding can elicit a variety of pharmacological and biologicaleffects in vitro and in vivo. When administered to the brain of liveanimals (intracerebroventricularly (icv) or into the amygdala), NPYproduces anxiolytic effects in established animal models of anxiety suchas the elevated plus-maze, Vogel punished drinking and Geller-Seifter'sbar-pressing conflict paradigms (Heilig, M. et. al. Psychopharmacology1989, 98, 524; Heilig, M. et. al. Reg. Peptides 1992, 41, 61; Heilig, M.et. al. Neuropsycho-pharmacology 1993, 8, 357). Thus compounds thatmimic NPY are postulated to be useful for the treatment of anxiolyticdisorders.

The immunoreactivity of neuropeptide Y is notably decreased in thecerebrospinal fluid of patients with major depression and those ofsuicide victims (Widdowson, P. S. et. al. Journal of Neurochemistry1992, 59, 73), and rats treated with tricyclic antidepressants displaysignificant increases of NPY relative to a control group (Heilig, M. et.al. European Journal of Pharmacology 1988, 147, 465). These findingssuggest that an inadequate NPY response may play a role in somedepressive illnesses, and that compounds that regulate the NPY-ergicsystem may be useful for the treatment of depression.

Neuropeptide Y improves memory and performance scores in animal modelsof learning (Flood, J. F. et. al. Brain Research 1987, 421, 280) andtherefore may serve as a cognition enhancer for the treatment ofneurodegenerative diseases such as Alzheimer's Disease (AD) as well asAIDS-related and senile dementia.

Elevated plasma levels of NPY are present in animals and humansexperiencing episodes of high sympathetic nerve activity such assurgery, newborn delivery and hemorrhage (Morris, M. J. et. al. Journalof Autonomic Nervous System 1986, 17, 143). Thus chemical substancesthat alter the NPY-ergic system may be useful for alleviating migraine,pain and the condition of stress.

Neuropeptide Y also mediates endocrine functions such as the release ofluteinizing hormone (LH) in rodents (Kalra, S. P. et. al. Frontiers inNeuroendrocrinology 1992, 13, 1). Since LH is vital for mammalianovulation, a compound that mimics the action of NPY could be useful forthe treatment of infertility, particularly in women with so-calledluteal phase defects.

Neuropeptide Y is a powerful stimulant of food intake; as little asone-billionth of a gram, when injected directly into the CNS, causessatiated rats to overeat (Clark, J. T. et. al. Endocrinology 1984, 115,427; Levine, A. S. et. al. Peptides 1984, 5, 1025; Stanley, B. G. et.al. Life Sci. 1984, 35, 2635; Stanley, B. G. et. al. Proc. Nat. Acad.Sci. USA 1985, 82, 3940). Thus NPY is orexigenic in rodents but notanxiogenic when given intracerebroventricularly and so antagonism ofneuropeptide receptors may be useful for the treatment of diabetes andeating disorders such as obesity, anorexia nervosa and bulimia nervosa.

In recent years, a variety of potent, structurally distinct smallmolecule Y1 antagonists has been discovered and developed (Hipskind, P.A. et. al. Annu. Rep. Med. Chem. 1996, 31, 1-10; Rudolf, K. et. al. Eur.J. Pharmacol. 1994, 271, R11; Serradeil-Le Gal, C. et. al. FEBS Lett.1995, 362, 192; Wright, J. et. al. Bioorg. Med. Chem. Lett. 1996, 6,1809; Poindexter, G. S. et. al. U.S. Pat. No. 5,668,151; Peterson, J. M.et. al. WO9614307 (1996)). However, despite claims of activity in rodentmodels of feeding, it is unclear if inhibition of a feeding response canbe attributed to antagonism of the Y1 receptor.

Several landmark studies strongly suggest that an “atypical Y1” receptorand/or the Y5 receptor, rather than the classic Y1 receptor, isresponsible for invoking NPY-stimulated food consumption in animals. Ithas been shown that the NPY fragment NPY2-36 is a potent inducer offeeding despite poor binding at the classic Y1 receptor (Stanley, B. G.et. al. Peptides 1992, 13, 581). Conversely, a potent and selective Y1agonist has been reported to be inactive at stimulating feeding inanimals (Kirby, D. A. et. al. J. Med. Chem. 1995, 38, 4579). Morepertinent to the invention described herein, [D-Trp³²]NPY, a selectiveY5 receptor activator has been reported to stimulate food intake wheninjected into the hypothalamus of rats (Gerald, C. et. al. Nature 1996,382, 168). Since [D-Trp³²]NPY appears to be a full agonist of the Y5receptor with no appreciable Y1 activity, the Y5 receptor ishypothesized to be responsible for the feeding response. Accordinglycompounds that antagonize the Y5 receptor should be effective ininhibiting food intake, particularly that stimulated by NPY.

A variety of structurally diverse compounds that antagonize the Y5receptor have been described in various publications. In PCT WO97/19682, aryl sulfonamides and sulfamides derived from arylalkylaminesare described as Y5 antagonists and are reported to reduce foodconsumption in animals. In. PCT WO 97/20820, PCT WO 97/20822 and PCT WO97/20823, sulfonamides containing heterocyclic systems such asquinazolin-2,4-diazirines, are likewise claimed as Y5 antagonists andreported to reduce feeding. In PCT WO 99/10330, a series of heterocyclicketones is claimed to be NPY Y5 antagonists. In PCT WO 99/01128, certaindiarylimidazole derivatives are claimed as a new class of NPY specificligands. In PCT WO 98/35944, a series of α-alkoxy and α-thioalkoxyamidesare claimed to be NPY Y5 receptor antagonists. In PCT WO 98/35957, aseries of amide derivatives are claimed as selective neuropeptide Yreceptor antagonists; however, these compounds are structurallydifferent from the compounds of this invention. The amides and amines ofthis invention that are described herein are novel molecular entitiesthat may have binding motifs that are different from these and other Y5ligands that have been disclosed in patent applications or publications.

SUMMARY OF THE INVENTION

The present invention is related to compounds of formula A

-   R₁ is independently selected from the group consisting of hydrogen;    hydroxy; halo; C₁₋₈alkyl; substituted C₁₋₈ alkyl wherein the    substituent is selected from halo, such as chloro, bromo, fluoro and    iodo; C₁₋₈alkoxy; substituted C₁₋₈ alkoxy wherein the substituent is    selected from halo, such as chloro, bromo, fluoro and iodo;    trifluoroalkyl; C₁₋₈alkylthio and substituted C₁₋₈alkylthio wherein    the substituent is selected from halo, such as chloro, bromo, fluoro    and iodo, trifluoroC₁₋₈alkyl and C₁₋₈alkoxy; C₃₋₆cycloalkyl;    C₃₋₈cycloalkoxy; nitro; amino; C₁₋₆alkylamino; C₁₋₈dialkylamino;    C₄₋₈cycloalkylamino; cyano; carboxy; C₁₋₅alkoxycarbonyl;    C₁₋₅alkylcarbonyloxy; formyl; carbamoyl; phenyl and substituted    phenyl wherein the substituent is selected from halo, hydroxyl,    nitro, amino and cyano;-   n is 1-2-   B₁ is hydrogen;-   B₂ is hydrogen;

or B₁ and B₂ may be methylene and joined together form a five orsix-membered ring;

-   m 0-3-   R₂ is independently selected from the group consisting of hydrogen;    hydroxy; C₁₋₆alkyl; C₂₋₆alkenyl; halo, such as fluoro and chloro;    C₃₋₇cycloalkyl; phenyl; substituted phenyl wherein the substituent    is, selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy, trifluoroC₁₋₆alkyl,    cyano, nitro, amino, C₁₋₆alkylamino, and C₁₋₆dialkylamino; naphthyl;    substituted naphthyl wherein the substituent is selected from halo,    C₁₋₆alkyl, C₁₋₆alkoxy, trifluoroC₁₋₆alkyl, cyano, nitro, amino,    C₁₋₆alkylamino, and C₁₋₆dialkylamino; phenoxy; substituted phenoxy    wherein the substituent is selected from halo, C₁₋₆alkyl,    C₁₋₆alkoxy, trifluoroC₁₋₆alkyl, cyano and nitro; a heteroaryl group    such as pyridyl, pyrimidyl, furyl, thienyl, and imidazolyl;    substituted heteroaryl wherein the substitutent is selected from    C₁₋₆alkyl and halo; and heterocycloalkyl such as pyrrolidino or    piperidino;-   Y is methylene (—CH₂—) or carbonyl (C═O)-   L is selected from the group consisting of

C₁₋₈alkylene; C₂₋₁₀alkenylene; C₂₋₁₀alkynylene; C₃₋₇cycloalkylene;

C₃₋₇cycloalkylC₁₋₄alkylene;

arylC₁₋₄alkylene;

α-aminoC₄₋₇alkylene;

(N-methylene)piperidin-4-yl;

(N-methylene)piperazin-4-yl;

(N-methylene)pyrrolidin-3-yl;

(N-methylene)-4-acetyl-piperidin-4-yl;

and (N-methylene)piperidin-4,4-diyl;

-   Z is selected from the group consisting of:

aryl;

N-sulfonamido;

N-(aryl)sulfonamido;

arylamido;

arylureido;

arylacetamido:

(aryloxy)carbonylamino;

2,3-dihydro-2-oxo-1H-benzimidazol-1-yl;

and 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl;

The aryl group in each case may be substituted as shown.

-   R₃ is independently selected from the group consisting of C₁₋₈alkyl;    substituted C₁₋₈alkyl wherein the substituent is selected from    C₁₋₈alkoxy and halo; cycloalkyl; substituted cycloalkyl wherein the    substituent is selected from C₁₋₈alkoxy and halo; naphthyl;    substituted naphthyl wherein the substituent is selected from halo,    nitro, amino and cyano; heteroaryl wherein the heteroaryl group is    selected from pyridyl, pyrimidyl, furyl, thienyl and imidazolyl; and    substituted heteroaryl wherein the substituent is selected from    halo, nitro, amino and cyano;-   R₄ is independently selected from the group consisting of hydrogen;    C₁₋₈alkyl; substituted C₁₋₈alkyl wherein the substituent is selected    from alkoxy and halo; hydroxy; halogen; cyano; nitro; amino;    C₁₋₈alkylamino and C₁₋₈dialkylamino; C₁₋₈alkoxy; substituted    C₁₋₈alkoxy wherein the substituent is halo; hydroxy; halogen; cyano,    nitro; amino and C₁₋₈alkylamino and C₁₋₈dialkylamino;-   R₅ is independently selected from the group consisting of hydrogen;    C₁₋₈alkyl; C₁₋₈alkylcarbonyl; aroyl; carbamoyl; amidino;    (C₁₋₈alkylamino)carbonyl; (arylamino)carbonyl and    arylC₁₋₈alkylcarbonyl;-   R₆ is independently selected from the group consisting of hydrogen    and C₁₋₈alkyl;-   p is 1-3;-   q is 1-3;

and enantiomers, diastereomers, and pharmaceutically acceptable saltsthereof,

provided that:

when L is C₁₋₈alkylene, C₂₋₁₀alkenylene, C₂₋₁₀alkynylene,C₃₋₇cycloalkylene,

C₃₋₇cycloalkylC₁₋₄alkylene, arylC₁₋₄alkylene or α-aminoalkylene;

-   -   then Z is phenyl, N-sulfonamido or N-(aryl)sulfonamido;

when L is (N-methylene)piperazin-4-yl;

-   -   then Z is phenyl or naphthyl;

when L is (N-methylene)pyrrolidin-3-yl or (N-methylene)piperidin-4-yl;

-   -   then Z is N-sulfonamido, N-(aryl)sulfonamido,        2,3-dihydro-2-oxo-1H-benzimidazol-1-yl; benzamido, phenylureido,        phenylacetamido or (phenoxy)carbonylamino;

when L is (N-methylene)-4-acetyl-piperidin-4-yl;

-   -   then Z is phenyl or naphthyl and Y is carbonyl;

when L is (N-methylene)piperidin-4,4-diyl;

-   -   then Z is 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl and Y is        carbonyl;

and when B₁ and B₂ are both methylene thus forming a six-membered ring(an aminotetralin) and when L is selected from the group consisting ofC₁₋₈alkylene; C₂₋₁₀alkenylene; C₂₋₁₀alkynylene or arylC₁₋₄alkylene;

-   -   then Z cannot be N-sulfonamido, N-(aryl)sulfonamido or phenyl;

all enantiomers and diastereomers of compounds of formula A are part ofthe present invention, as are pharmaceutically acceptable salts thereof.

Preferred compounds among the compounds of this invention are thosewherein B₁ and B₂ form a six-membered ring and m=1-3.

As used herein unless otherwise noted the terms “alkyl” and “alkoxy”whether used alone or as part of a substituent group, include straightand branched chains having 1-8 carbon atoms. For example, alkyl radicalsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl, pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl,neopentyl, hexyl, 1-methylpentyl, 3-methylpentyl. Alkoxy radicals areoxygen ethers formed from the previously described straight or branchedchain alkyl groups. The term “aryl” is intended to include phenyl andnaphthyl and aroyl is intended to include arylacyl. The term “acyl” isintended to include C₁₋₈alkylcarbonyl. The term “halo”, unless otherwiseindicated, includes bromo, chloro, fluoro and iodo. The term“cycloalkyl” is intended to include cycloalkyl groups having 3-7 carbonatoms. With reference to substituents, the term “independently” meansthat when more than one of such substituent is possible, suchsubstituents may be the same or different from each other.

Those compounds of the present invention which contain a basic moietycan be converted to the corresponding acid addition salts by techniquesknown to those skilled in the art. Suitable acids which can be employedfor this purpose include hydrochloric, hydrobromic, hydriodic,perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic,p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic,2-acetoxybenzoic, or saccharin, and the like. In general, the acidaddition salts can be prepared by reacting the free base of compounds offormula A with the acid and isolating the salt.

Pharmaceutical compositions containing one or more of the compounds ofthe invention described herein as the active ingredient can be preparedby intimately mixing the compound or compounds with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

For the treatment of disorders of the central nervous system, thepharmaceutical compositions described herein will typically contain from1 to about 1000 mg of the active ingredient per dosage; one or moredoses per day may be administered. Determination of optimum doses andfrequency of dosing for a particular disease state or disorder is withinthe experimental capabilities of those knowledgeable in the treatment ofcentral nervous system disorders. The preferred dose range is 1-100mg/kg.

As modulators of the NPY5 receptor, the compounds of Formula A areuseful for treating feeding disorders such as obesity, anorexia nervosaand bulimia nervosa, and abnormal conditions such as epilepsy,depression, anxiety and sexual/reproductive disorders in whichmodulation of the NPY5 receptor may be useful. The compounds competewith the endogenous ligands NPY and PYY and possibly non-endogenousligands, and bind to the NPY5 receptor. In addition, the compoundsdemonstrate antagonist activity by antagonizing the action of NPY uponbinding to the Y5 receptor.

The compounds described herein are ligands of the NPY5 receptor, but arenot necessarily limited solely in their pharmacological or biologicalaction due to binding to this or any neuropeptide, neurotransmitter orG-protein coupled receptor. For example, the described compounds mayalso undergo binding to dopamine or serotonin receptors. The compoundsdescribed herein are potentially useful in the regulation of metabolicand endocrine functions, particularly those associated with feeding, andas such, may be useful for the treatment of obesity. In addition, thecompounds described herein are potentially useful for modulating otherendocrine functions, particularly those controlled by the pituitary andhypothalamic glands, and therefore may be useful for the treatment ofinovulation/infertility due to insufficient release of luteinizinghormone (LH) or luteal phase defect.

The present invention comprises pharmaceutical compositions containingone or more of the compounds of Formula A. In addition, the presentinvention comprises intermediates used in the manufacture of compoundsof Formula A.

Examples of particularly preferred compounds of formula A include:

DETAILED DESCRIPTION OF THE INVENTION

The amines and amides of formula A that comprise this invention aresynthesized via several distinct chemical syntheses as outlined inSchemes 1-26; each synthetic route consists of several sequentialchemical operations that can be generalized as described below. In casesin which B₁ and B₂ together form a six-membered ring or a five-memberedring (an aminotetralin or an aminoindane, respectively), the generalsynthesis entails the following operations:

-   -   Introduction of the a-substituent onto the tetralone (or        indanone) nucleus    -   Conversion to the corresponding α-substituted-β-aminotetralin        (or α-substituted-aminoindane)    -   Acylation of the aminotetralin (or aminoindane) to afford amides        of formula A    -   Reduction to produce amines of formula A

Protecting group manipulations may be needed at various stages of thesyntheses.

In cases where B₁ and B₂ are hydrogen, the general synthesis consists ofthe following operations:

-   -   Introduction of the α-substituent onto a phenylacetonitrile    -   Reduction to the corresponding β-substituted phenethylamine    -   Acylation of the phenethylamine to afford amides of formula A    -   Reduction to produce amines of formula A

Protecting group manipulations may be needed at various stages of thesyntheses.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS) and liquid chromatography (HPLC). In the descriptionsfor the preparation of compounds of this invention, ethyl ether,tetrahydrofuran and dioxane are common examples of an ethereal solvent;benzene, toluene, hexanes and cyclohexane are typical hydrocarbonsolvents and dichloromethane and dichloroethane are representativehalohydrocarbon solvents. In those cases wherein the product is isolatedas the acid addition salt the free base may be obtained by techniquesknown to those skilled in the art. In those cases in which the productis isolated as an acid addition salt, the salt may contain one or moreequivalents of the acid.

Specifically, an appropriately substituted β-tetralone (II) is reactedwith an aryl or heteroaryl aldehyde in the presence of a base such aspiperidine, in an inert halohydrocarbon, ethereal or hydrocarbonsolvent, such as benzene, from ambient temperature to reflux, to affordthe corresponding α-benzylidenyl-β-tetralone orα-heteroarylmethylidenyl-β-tetralone (III). The β-tetralone (III) isdissolved in an inert hydrocarbon, ethereal, ester or alcohol solvent,such as methanol, and reacted with hydrogen gas at a pressure fromambient pressure to 100 p.s.i. in the presence of a suitable catalystsuch as palladium on carbon. The reaction is performed at a temperaturefrom ambient temperature to reflux, to yield the desiredα-substituted-β-tetralone (IV) (Scheme 1).

An alternative method for the preparation of α-substituted-β-tetralones(IV) involves the reaction of an appropriately substituted β-tetralone(II) with a base such as pyrrolidine in an inert halohydrocarbon solventsuch as dichloromethane or hydrocarbon solvent such as benzene, underDean-Stark conditions (removal of water) or in an alcohol solvent suchas methanol, from ambient temperature to reflux, to afford enamine (V).Alkylation of enamine (V) is accomplished by reaction with a benzylic,heterocyclicalkyl or an allylic halide in an inert solvent such asacetonitrile, at a temperature from ambient temperature to reflux, toafford the α-substituted-β-iminium salt (VI). Hydrolysis of the salt(VI) to produce the desired α-substituted-β-tetralone product (IV) isaccomplished by reaction of (VI) with water and an inorganic or organicacid such as hydrochloric or glacial acetic acid in an inerthydrocarbon, ethereal, alcohol or halohydrocarbon solvent, or a mixturethereof, such as methanol and dichloromethane (Scheme 1).

The α-substituted-β-tetralones (IV) are converted to the correspondingaminotetralins via reaction with an ammonium salt such as ammoniumacetate in the presence of a reducing agent such as sodiumcyanoborohydride, for example, in an inert halohydrocarbon, hydrocarbon,ethereal or alcohol solvent such as methanol to produce thecis-aminotetralin (VII). In some, cases, the trans-aminotetralin (VIII)is also formed as a minor product; both sets of diastereomers are partof this invention. The aminotetralins (VII) can also be isolated as acidaddition salts by treatment with an organic or an inorganic acid, suchas trifluoroacetic acid or hydrochloric acid, for example (Scheme 2).

-   Compounds in which m=0 are prepared from an appropriately    substituted aminotetralin (VII; m=0) starting from 1-tetralones    using the synthetic sequence shown in Scheme 2a.    Substituted phenethylamines (XI) are prepared by reacting an    appropriately substituted phenylacetonitrile (IX) with an aryl or    heteroaryl aldehyde in the presence of a base, such as sodium    methoxide, in an inert alcohol solvent, such as methanol, at a    temperature from ambient temperature to reflux, to afford    α,β-unsaturated nitrite (X). Subsequent reduction of nitrile (X),    for example, via reaction with hydrogen gas in the presence of a    platinum oxide catalyst at a pressure from atmospheric pressure to    approximately 100 psi, in an inert solvent such as aqueous alcohol,    at a temperature from ambient temperature to reflux, affords    5-substituted phenethylamine (XI). Alternatively, reaction of    phenylacetonitrile (X) with an arylalkyl-, heteroarylalkyl- or alkyl    halide, for example, such as allyl bromide in, the presence of a    base such as sodium methoxide or sodium hydride, in an inert solvent    such as tetrahydrofuran or acetonitrile respectively, at a    temperature from ambient to reflux, affords a-substituted    phenylacetonitrile (XII). Subsequent reduction of nitrile (XII), for    example, by hydrogenolysis, produces β-substituted    phenethylamine (XI) (Scheme 3).

The β-aminotetralins (VII) and the phenethylamines (XI) described aboveare acylated via. suitable amidation methods (see Gross and Meienhofer,Eds., “The Peptides”, Vols. 1-3, Academic Press, New York, N.Y.,1979-1981). A carboxylic acid is converted to an activated ester viapeptide coupling methods known to those skilled in the art, andsubsequently reacted with an aminotetralin (VII) or phenethylamine (XI),to afford the corresponding amides.

For example, a carboxylic acid such astrans-4-(2-fluorobenzenesulfonamido)methylcyclohexane carboxylic acid or4-(tert-butoxycarbonyl)aminomethylcyclohexane carboxylic acid is reactedwith HSTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate and an appropriate phenethylamine (XI), in thepresence of a base such as diisopropylethylamine, in an inert solventsuch as N,N-dimethylformamide, at a temperature from ambient temperatureto reflux, to afford amide (XIII) or amide (XIV) respectively. Cleavageof the BOC (butoxycarbonyl) protecting group from carbamate (XIV) withtrifluoroacetic acid produces the free amine, which is sulfonylated toyield amide (XIII).

The N-substituted phenethylamine compounds A of the invention areprepared via reduction of amide (XIII) by reaction with a suitablereducing agent such as borane-tetrahydrofuran complex or lithiumaluminum hydride in an inert hydrocarbon solvent such as toluene orethereal solvent such as tetrahydrofuran, at a temperature from ambienttemperature to reflux. The final product can be isolated as an acidaddition salt upon treatment with a suitable organic acid such astrifluoroacetic acid or an inorganic acid such as hydrochloric acid(Scheme 4).

Aminotetralin analogs (B₁ and B₂ each are methylene) are prepared usingthe chemistry described above but replacing the phenethylamine (XI)starting material with an aminotetralin (VII) (Scheme 5).

Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yland L=(N-methylene)piperidin-4-yl are prepared from β-aminotetralins(VII) or phenethylamines (XI) and[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6-7).For example, 4(2-keto-1-benzimidazolinyl)piperidine is reacted with abromoacetic acid ester, such as ethyl bromoacetate, in the presence ofan amine base, such as diisopropylethylamine, in an inert solvent suchas acetonitrile, at a temperature ranging from ambient temperature toreflux, to afford ethyl[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester issubjected to hydrolysis under basic conditions, for example, bytreatment with sodium hydroxide in an alcoholic solution such as aqueousmethanol, to yield, upon acidification with an inorganic or organic acidsuch as hydrochloric or acetic acid for example,[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. Thiscarboxylic acid is reacted directly with β-aminotetralins (VII) orphenethylamines (XI), in the presence of an amine base, under peptidecoupling conditions described above, to afford benzimidazolinones (XVII)and (XVIII) of formula A in which Y=carbonyl andL=(N-methylene)piperidin-4-yl (Schemes 6-7).

Compounds of formula A in which Y=methylene andL=(N-methylene)piperidin-4-yl andZ=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl are prepared by reduction ofamide (XVII) and amide (XVIII) with a reducing agent such asborane-tetrahydrofuran complex or lithium aluminum hydride as describedabove. The use of an aminotetralin (VII) starting material gives rise toproducts (XIX) (Scheme 8) whereas phenethylamines give the analogousamines (XX) (Scheme 9).

Compounds of formula A in which Y=carbonyl,L=(N-methylene)piperazin-4-yl and Z=phenyl are prepared by reacting aphenylpiperazine with a haloacetic acid ester, such as, for example,ethyl bromoacetate, in the presence of an amine base, such asdiisopropylethylamine, in an inert solvent such as acetonitrile, at atemperature ranging from ambient temperature to reflux, to afford ethyl(4-arylpiperazin-1-yl)acetate. This ester is subjected to hydrolysisunder basic conditions, for example, by treatment with sodium hydroxidein an aqueous methanol, to yield, upon acidification with an inorganicor organic acid such as hydrochloric or acetic acid for example,(4-arylpiperazin-1-yl)acetic acid. This carboxylic acid is reacted withβ-aminotetralins (VII) or phenethylamines (XI), in the presence of abase, such as triethylamine for example, under peptide couplingconditions described above, to afford arylpiperidines (XXI) and (XXII)respectively, of formula A in which Y=carbonyl,L=(N-methylene)piperazin-4-yl and Z=aryl or substituted aryl (Schemes10-11).

Compounds of formula A in which Y=methylene,L=(N-methylene)piperazin-4-yl and Z=aryl are prepared by reduction ofamides (XXI) and (XXII) with a reducing agent such asborane-tetrahydrofuran complex or lithium aluminum hydride (see Scheme9) to afford aminotetralins (XXIII) and phenethylamines (XIV)respectively (Schemes 12-13).

Replacement of 4-arylpiperazines with 4-arylpiperidines in Schemes 10and 11 affords tetralinamides (XXV) and phenethylamides (XXVI) offormula A in which L=(N-methylene)piperidin-4-yl, Z=aryl and Y=carbonyl(Schemes 14-15).

Separately, reduction of amides (XXV) and (XXVI) with a reducing agentsuch a boranetetrahydrofuran complex, affords amines (XXVII) and(XXVIII) of formula A in which L=(N-methylene)piperidin-4-yl, Z=aryl andY=methylene (Scheme 16).

Compounds of formula A in which Y=carbonyl,L=(N-methylene)pyrrolidin-3-yl and Z=N-(aryl)sulfonamido are prepared byreacting a suitably protected aminopyrrolidine, such as(3-t-butoxycarbonylamino)pyrrolidine with a haloacetic acid ester, suchas, for example, ethyl bromoacetate, in the presence of an amine base,such as diisopropylethylamine, in an inert solvent such as acetonitrile,at a temperature ranging from ambient temperature to reflux, to affordethyl [(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetate. This ester issubjected to hydrolysis under basic conditions, for example, bytreatment with sodium hydroxide in an aqueous methanol, to yield, uponacidification with an inorganic or organic acid such as hydrochloric oracetic acid for example,[(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetic acid. This carboxylicacid is reacted with β-aminotetralins (VII) or phenethylamines (XI), inthe presence of a base, such as triethylamine for example, under peptidecoupling conditions described above, to afford tetralinamides (XXIX) andphenethyamides (XXX) respectively. Subsequent treatment with an organicor inorganic acid, such as trifluoroacetic acid and hydrochloric acidfor example, produces the free terminal amines (XXXI) and (XXXII). Thesematerials are sulfonylated by reaction with sulfonyl halides such asbenzenesulfonyl chloride for example, in the presence of a base, toafford tetralinamides (XXXIII) and phenethylamides (XXXIV) (Schemes17-18).

Separately, reduction of amides (XXXIII) and (XXXIV) with a reducingagent such a borane-tetrahydrofuran complex, affords amines (XXXV) and(XXXVI) of formula A in which L=N-(methylene)pyrrolidin-3-yl andZ=sulfonamido or (aryl)sulfonamido, Y=methylene (Scheme 19).

Tetralinamides and phenethylamides of formula A in which Y=carbonyl,L=(N-methylene)pyrrolidin-3-yl and Z=benzamido, phenylureido,phenylacetamido and phenoxycarbonylamino (or butoxycarbonylamino) areprepared by reacting amines (XXXI) and (XXXII) respectively, in an inertsolvent at a temperature from ambient temperature to reflux, in thepresence of a base such as an amine or hydroxide, with an aroyl halide,an arylisocyanate, an arylacetyl halide or a chloroformate such asphenylchloroformate (or di-tert-butyl dicarbonate) to afford benzamides(XXXVII) and (XXXXI), phenylureas (XXXVIII) and (XXXXII),phenylacetamides (XXXIX) and (XXXXIII) and phenylcarbamate (XXXX) and(XXXIV) respectively (Schemes 20-21).

Compounds of formula A in which Y=methylene,L=N-(methylene)pyrrolidin-3-yl and Z=benzamido, phenylureido,phenylacetamido and phenylcarbonylamino (or butoxycarbonylamino) areprepared by reducing amides (XXXI) and (XXXII) to their respectiveamines (XXXXV) and (XXXXVI) by treatment With a reducing agent such asborane-tetrahydrofuran complex or lithium aluminum hydride. Amines(XXXXV) and (XXXXVI) are subsequently separately reacted with an aroylhalide, an arylisocyanate, an arylacetyl halide or an arylchloroformate(or carbonate such as di-tert-butyl carbonate), in the presence of abase in an inert solvent as described in Scheme 20-21, to affordbenzamides (XXXXVII) and (XXXXXI), phenylureas (XXXXVIII) and (XXXXXII),phenylacetamides (XXXXIX) and (XXXXXIII) and phenylcarbamates (XXXXX)and (XXXXXIV), respectively (Schemes 22-24).

Substituting an appropriately protected aminopiperidine, such as(4-t-butoxycarbonylamino)piperidine for (3-t-butoxycarbonylamino)pyrrolidine in Schemes 17-24 affords compounds offormula A in which L=(N-methylene)piperidin-4-yl, Y=methylene orcarbonyl and Z=N-(aryl)sulfonamido, sulfonamido, benzamido,phenylureido, phenylacetamido or (phenoxy)carbonylamino.

Compounds of formula A in which Y=carbonyl,L=(N-methylene)piperidin-4,4-diyl andZ=1-aryl-2,3-dihydro-4oxo-imidazol-5,5-diyl are prepared by reacting1-aryl-1,3,8-triazaspiro-{4,5}decan-4one with a haloacetic acid ester,such as ethyl brornoacetate, in the presence of an amine base, such asdiisopropylethylamine, in an inert solvent such as acetonitrile, at atemperature from ambient temperature to reflux, to afford ethyl(1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetate. This ester issubjected to hydrolysis under basic conditions, for example, bytreatment with sodium hydroxide in an alcoholic solution such as aqueousmethanol, to yield upon acidification with an inorganic or organic acidsuch as hydrochloric or acetic acid for example,(1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetic acid. Thiscarboxylic acid is reacted directly with β-tetralins (VII) orphenethylamines (XI), in the presence of a base such as triethylaminefor example, under peptide coupling conditions described above, toafford aminotetalinamides (XXXXXV) and phenethylamides (XXXXXVI)respectively, of formula A in which Y=carbonyl,L=(N-methylene)piperidin-4,4-diyl andZ=1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl (Schemes 25-26).

Compounds of formula A in which L =(N-methylene)-4-acetyl-piperidin-4-yland Z=phenyl are prepared by reacting 4-acetyl-4-phenylpiperidine with ahaloacetic acid ester, such as, for example, ethyl bromoacetate, in thepresence of an amine base, such as diisopropylethylamine, in an inertsolvent such as acetonitrile, at a temperature ranging from ambienttemperature to reflux, to afford ethyl[(4-acetyl-4-phenylpiperidin-1-yl]acetate. This ester is subjected tohydrolysis under basic conditions, for example, by treatment with sodiumhydroxide in an aqueous methanol, to yield, upon acidification with aninorganic or organic acid such as hydrochloric or acetic acid forexample, H4-acetyl-4-phenylpiperidin-1-ylacetic acid. This carboxylicacid is reacted with 13-aminotetralins (VII) or phenethylamines (XI), inthe presence of a base, such as triethylamine for example, under peptidecoupling conditions described above, to afford(tetralinamido)arylpiperidines (XXXXXVII) and(phenethylamido)arylpiperidines (XXXXXVIII) respectively, of formula Ain which Y=carbonyl, L=(N-methylene)-4-acetyl-piperidin-4-yl andZ=phenyl (Schemes 27-28).

Other compounds of this invention having the formula A can be preparedusing the methods described herein; modifications of the experimentalprotocols described above are known or obvious or within the ability ofthose skilled in the art. For example, a variety of β-tetralones areknown or readily prepared by reaction of phenylacetic acids withethylene gas in the presence of a Lewis acid (for example, Stjernlof, P.et. al. J. Med. Chem. 1995, 38, 2202); these compounds can be directlyconverted to aminotetralins (VII) via reductive amination (Scheme 2).Phenethylamine intermediates (XI) are accessible fromphenylacetonitriles using literature methods (Jounral, Hawes andWibberley, J. Chem. Soc. C. 1966, 315 and 320; also see J. Am. Chem.Soc. 1989, 111, 5954 and Synthesis 1997, 11, 1268) and can be used toprepare compounds of formula A in which B₁ and B₂ are both hydrogen(Scheme 3). Compounds in which the R₁ group(s) is varied can be obtainedusing the chemistry described above; in some cases, protecting groupmanipulations are used and these are obvious or known to those skilledin the art. Examples include masking an amine group as a carbamate,amide or phthalamide, and masking an hydroxyl group as an ether orester. Other R₁ substituents are available through functional groupmanipulations such as, for example, reduction of a nitro group to anamine or dehydration of an amide to a nitrile.

Variation of the R₂ group is readily accomplished by using substitutedbenzaldehydes, naphthylaldehydes and heteroaryl carboxaldehydes, or byusing alkyl, alkylenic, alkynylic and benzylic halides, or by usingphenoxyalkyl and haloalkyl halides in Schemes 1 and 3. Compounds inwhich the L group is varied, are derived from piperazines, piperidinesor pyrrolidines as described in Schemes 6, 10, 14, 17 and 25. Compoundsin which L is alkylene, alkenylene, alkynylene, cycloalkylene orcycloalkylalkylene are derived from amino-carboxylic acids such asaminohexanoic acid, aminohexenoic acid, aminohexynoic acid. Compounds inwhich L is a-aminoalkylene are derived from amino acids such as lysinewhich can be used in the racemic or enantiomeric form.

Compounds of formula A where Z is sulfonamido or (aryl)sulfonamido, inwhich either the R₃ or the R₄ group is varied, are accessible bysulfonylation; there are hundreds of sulfonyl halides or sulfonic acidsthat are commercially available and more that are known. Compounds offormula A where Z is sulfonamido or (aryl)sulfonamido, in which the R₃substituent is heteroaryl can be prepared by substituting a pyridinyl,thienyl or furyl sulfonylchloride for a benzenesulfonamide as describedin Schemes 4-5. Similarly, alkylsulfonyl and cycloalkylsulfonyl halides,alone or in the presence of an activating agent such as a Lewis acid,can be used to prepare sulfonamides of formula A in which the R₃substituent is alkyl or cycloalkyl respectively. Compounds in which Z isphenyl or aryl are obtained directly from arylpiperazines andarylpiperidines as described in Schemes 10 and 14 respectively; hundredsof arylpiperazines and arylpiperidines are known or commerciallyavailable and can be used to make compounds of this invention. Compoundsof formula A where Z is benzamido, phenylureido, phenylacetamido,(phenoxy)carbonylamino are prepared from aroyl halides, isocyanates,phenylacetyl halides and chloroformates as described in Schemes 20-21and 23-24 and hundreds of reagents of these kinds are commerciallyavailable or known.

Compounds of formula A in which B₁ and B₂ are joined together to form afive-membered ring (an aminoindane) are prepared starting from anindanone and using the chemistry described herein. It is preferable touse a symmetrical indan-2-one to avoid the formation of regiochemicalisomers which are difficult to separate.

EXAMPLES

The following examples describe the invention in greater detail and areintended to illustrate the invention, but not to limit it. All compoundswere identified by a variety of methods including nuclear magneticresonance spectroscopy, mass spectrometry and, in some cases, infraredspectroscopy and elemental analysis. Nuclear magnetic resonance (300 MHzNMR) data are reported in parts per million downfield fromtetramethylsilane. Mass spectra data are reported in mass/charge (m/z)units. Unless otherwise noted, the materials used in the examples wereobtained from readily available commercial sources or synthesized bystandard methods known to those skilled in the art.

Examples 1-2

2-Amino-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthenyl-(2S)-hexanamide bis-hydrochloride 7

N-[5-amino-6-[[cis-[1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]amino]hexyl-2-fluorobenzenesulfonamidetris-hydrochloride 8

A. 6-Methoxy-β-tetralone 1 (2.0 g, 11.3 mmol) and diisopropylethylamine(0.20 mL, 1.1 mmol) were dissolved in benzene (60 mL) with stirring in a100 mL round-bottom flask. 3-Pyridylcarboxaldehyde (1.1 mL, 11.7 mmol)was added and the reaction vessel was flushed with argon and aDean-Stark trap with reflux condenser was attached. The mixture washeated at reflux for 19 hours. After cooling, HPLC analysis indicatedthat no products had formed. Piperidine (0.094 mL, 1.1 mmol) was addedat this time and heating at reflux was continued for 23 hours. Thesolvents were removed in vacuo to yield a glassy orange solid.Chromatographic purification [silica gel column (dimensions 5×29 cm)eluting with a gradient of: 100% hexane (400 mL), 75%/25% hexane/ethylacetate (v/v) (400 mL), 50%/50% hexane/ethyl acetate (v/v) (400 mL),25%/75% hexane/ethyl acetate (v/v) (400 mL), and finally with 100% ethylacetate] was performed. After evaporation of the appropriate fractions,3,4-dihydro-6-methoxy-1-((3-pyridinyl)methylidenyl)-2-naphthalenone 2(1.484 g, 5.59 mmol) was obtained as an orange oil which solidified uponstanding in the refrigerator. MS (MH⁺) 266; ¹H NMR (CDCl₃) δ 2.67 (t,2H), 3.02 (t, 2H), 3.83 (s, 3H), 6.60 (dd, 1H), 6.82 (d, 1H), 7.19 (m,2H), 7.51 (s, 1H), 7.71 (d, 1H), 8.49 (dd, 1H), 8.65 (d, 1H).

B. The naphthalen-2-one 2 (1.442 g, 5.44 mmol) obtained above wasdissolved in absolute ethanol (50 mL) and transferred to a 250 mL Parrhydrogenation bottle. Separately, ethanol was carefully added to 10%palladium on carbon (0.020 g) and this slurry was added to the Parrbottle. The mixture was hydrogenated under a pressure of 50 psi for 16hours. The catalyst was removed by filtration over Celite. Spectroscopicevidence indicated the presence of some starting material and so morepalladium catalyst (0.081 g) was added to the ethanol solution and thehydrogenation was repeated for 20 hours. The catalyst was then removedby filtration over Celite. Removal of the solvents in vacuo yielded3,4-dihydro-6-methoxy-1 -(3-pyridinylmethyl)-2(1 H)-naphthalenone 3 asan orange oil which was used in the next step without furtherpurification. MS (MH⁺) 268.

C. Naphthalen-2-one 3 obtained above was dissolved in methanol (275 mL)in a 1 L round-bottom flask. Ammonium acetate (4.27 g, 55.4 mmol) wasadded to the stirred methanol solution and was allowed to completelydissolve before proceeding. Sodium cyanoborohydride (1.703 g, 27.5 mmol)was then added to the methanol solution. The reaction vessel was flushedwith nitrogen and the solution refluxed for 18 hours. The solvents werethen removed in vacuo to yield a yellow solid which was dissolved inethyl ether (500 mL) and 0.1 M sodium hydroxide solution (275 mL).. Theorganic layer was removed and washed with an additional 0.1 M sodiumhydroxide solution (275 mL) and with water (250 mL). The combinedaqueous washes were back extracted with ethyl ether (3×100 mL). Theorganic extracts were combined and dried over sodium sulfate. Thesolvents were removed in vacuo and the residue was taken up in ethylether and a minimum amount of dichloromethane. An excess of 1 M hydrogenchloride in ethyl ether was added and a dark tan precipitate formed. Thesolvents were removed in vacuo and the resulting solid was trituratedwith ether and dried in a vacuum oven to yield1,2,3,4-tetrahydro-6-methoxy-1 -(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 4 as a tan-orange solid (1.208 g, 3.54 mmol) MS (MH⁺)269; ¹H NMR (DMSO-d₆) δ 1.95-2.20 (m, 2H), 2.68-3.29 (m, 4H), 3.30-3.48(m, 2H), 3.69 (s, 3H), 5.98 (d, 1H), 6.41 (dd, 1H), 6.75 (d, 1H), 7.98(dd, 1H), 8.36 (d, 1H), 8.68-8.89 (m, 5H) (FIG. 1).

D. N-tert-Butoxycarbonyl-L-Lysine (2.49 g, 10.1 mmol) was placed in a200 mL round-bottom flask. A magnetic stir bar was added followed by 10mL dioxane and 21 mL 1 N sodium hydroxide solution. The solution wasstirred for several minutes until complete dissolution had occurred. Asolution of 2-fluorobenzenesulfonyl chloride (2.00 g, 10.3 mmol) indioxane (11 mL) was added via pipette. The reaction vessel was flushedwith argon, capped and allowed to stir at ambient temperature forapproximately 1.5 hours. The stir bar was then removed and the solventevaporated under reduced pressure until only water remained. To thismixture water was added to bring the volume to about 50 mL and 1 Nhydrochloric acid (22 mL) was added which resulted in the formation of agooey precipitate. This mixture was extracted with methylene chloride(3×50 mL) and the combined organics were washed with 1N hydrochloricacid (1×50 mL) and then brine (1×50 mL). The organics were dried overmagnesium sulfate, filtered and concentrated in vacuo to yield thesulfonylated N-t-butoxycarbonyl-lysine 5 (3.93 g, 9.7 mmol) as anoff-white glassy semi-solid. NMR(d₆-DMSO): δ 12.42 (s, 1H), 7.90 (t,1H), 7.79 (t, 1H), 7.71 (m, 1 H), 7.49-7.34 (m, 2H), 7.02 (d, 1 H), 3.78(m, 1 H), 2.83 (m, 2H), 1.63-1.16 (m, 15H); MS: M-H =403.

E. The sulfonylated L-lysine 5 from the previous reaction (3.92 g, 9.69mmol) was placed in a 300 mL round-bottom flask along with1,2,3,4-tetrahydro-6-methoxy-1 -(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 4 (3.53 g, 1-0.34 mmol) and a stir bar.N,N-Dimethylformamide (DMF) (50 mL) was added followed bydiisopropylethylamine (5.6 mL, 32.1 mmol) and the mixture was stirred.After dissolution, 2-(1H-benzotriazole-1-yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate (HBTU) (3.72 g, 9.81 mmol) was added and the flaskwas flushed with argon, capped and allowed to stir at ambienttemperature for 30 minutes. Water (˜5 mL) was then added to quench thereaction and the solvents were removed in vacuo to give a brown oil.This material was purified by column chromatography on a silica gelcolumn (dimensions 6×12 cm) eluting with a gradient of methylenechloride-acetone-methanol. After evaporation of the appropriatefractions, adduct 6 (as a tan-green foam, 4.63 g, 7.07 mmol) wasobtained as a mixture of diastereomers. MS: MH⁺=655.

F. The sulfonylated lysino-tetralinamide 6 from the previous reaction(4.59 g, 7.01 mmol) was placed in a 200 mL round-bottom flask with astir bar and methylene chloride (100 mL) was added. With stirring, asolution of 95% TFA/5% H₂O (v/v) (10 mL) was added and the reactionmixture was allowed to stir under nitrogen at ambient temperature for3.5 hours. The reaction mixture was then concentrated in vacuo and theresidue was triturated with diethyl ether. The liquid was decanted andmore ether was added. The resultant solid was filtered and dried undervacuum to give the desired tetralinamide lysino-sulfonamidebis-hydrochloride 7 (4.28 g, 5.47 mmol) as a mixture of diastereomers. Aportion of this material (4.01 g) was separated into racemic sets ofdiastereomers via reverse-phase chromatography (Bondapak C18, 6×(40×100mm) column using a gradient of H₂O/CH₃CN (+0.1% TFA)). The appropriatefractions were isolated and lyophilized to yield diastereomer a (2.17 g,2.77 mmol) and diasteromers b (1.78 g, 2.27 mmol) as bis-TFA salts(absolute configurations of the diastereomers were not determined).Diastereomer a: de=96%; NMR(d₆-DMSO): δ 8.57 (m, 2H), 8.30 (s, 1 H),8.11 (br, 3H), 7.96 (t, 1 H), 7.80-7.64 (m, 3H), 7.55 (dd, 1H),7.48-7.32 (m, 2H), 6.71 (s, 1H), 6.58-6.46 (m, 2H), 4.03 (m, 1H), 3.79(m, 1H), 3.69 (s, 3H), 3.24 (m, 1H), 3.03-2.73 (m, 6H), 2.08-1.91 (m,1H), 1.85-1.58 (m, 3H), 1.53-1.31 (m, 4H); MS: MH+=555. Diastereomer b:de=100%; NMR(d₆-DMSO): δ 8.68 (d, 1H), 8.57 (d, 1H), 8.49 (s, 1H), 8.21(br, 3H), 8.01 (d, 1H), 7.93 (t, 1H), 7.78 (dt, 1H), 7.73 (m, 2H),7.52-7.37 (m, 2H), 6.75 (s, 1H), 6.56 (m, 2H), 3.99 (m, 1H), 3.85 (m, 1H), 3.71 (s, 3H), 3.23 (m, 1H), 3.08-2.76 (m, 6H), 2.00-1.59 (m, 4H),1.53-1.22 (m, 4H); MS: MH+=555 (FIG. 2).

G. Diastereomer a 7 from the previous reaction (2.02 g, 2.58 mmol) wasplaced in a 200 mL round-bottom flask along with a stir bar and THF (60mL) was added. After stirring, a solution of borane in THF (40 mL of a1M solution, 40 mmol) was added and the flask was flushed with nitrogenand a reflux condenser was attached. The mixture was heated at refluxfor 24 hours at which time an additional portion of the borane solution(10 mL) was added. The reaction mixture was heated at reflux for anadditional 14 hours. The reaction mixture was allowed to cool and water(10 mL) was carefully added to quench the reaction. Hydrochloric acid(20 mL of a 1N solution) was added and the reaction mixture was heatedat reflux for 2 hours. The solvents were removed in vacuo and theresidue was suspended in water (250 mL). This mixture was made slightlyacidic via the addition of 1N hydrochloric acid. This aqueous solutionwas washed with methylene chloride (3×250 mL) and the aqueous layer wasseparated. Ammonium hydroxide solution was added until the pH was basic.The water was then removed in vacuo giving a white solid. The resultantmaterial was triturated with methylene chloride and the borane saltsthat precipitated were removed by filtration. The remaining organicswere concentrated in vacuo to give the crude product as a foam. Thismaterial was purified by flash chromatography on a silica gel column(dimensions 6×11 cm) eluting with a gradient of methylenechloride-methanol-ammonium hydroxide. After evaporation of theappropriate fractions, the residue was treated with an excess ofethanolic-hydrogen chloride, followed by evaporation and drying undervacuum, to obtain aminotetralin sulfonamide 8 as a yellowtris-hydrochloride salt (0.898 g, 1.38 mmol). NMR(d₆-DMSO): δ 10.83 (br,1H), 10.08 (br, 1H), 8.80 (d, 1H), 8.73 (m, 4H), 8.43 (d, 1H), 7.97 (m,2H), 7.81 (t, 1H), 7.71 (m, 1H), 7.51-7.33 (m, 2H), 6.75 (s, 1H), 6.37(d, 1H), 5.83 (d, 1H), 3.80 (m, 1H), 3.71 -3.30 (m, 8H), 3.11 (m, 1 H),2.98-2.69 (m, 4H), 2.34-2.13 (m, 2H), 1.73-1.55 (m, 2H), 1.54-1.29 (m,4H); MS: MH+=541 (FIG. 2).

Example 3

N-[5-amino-6-[[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]amino]hexyl-2-fluorobenzenesulfonamidetris-hydrochloride 9

Aminotetralin sulfonamide 8 from the previous reaction (0.160 g, 0.246mmol) was placed in a 50 mL round-bottom flask along with a stir bar.Methylene chloride (25 mL) was added and the slurry was cooled on an icebath for several minutes. Boron tribromide in methylene chloride (1M,1.25 mL, 1.25 mmol) was added to the reaction. The flask was flushedwith argon, capped and allowed to warm up to ambient temperature and themixture was stirred over 16 hours at which time the reaction wasquenched by the addition of methanol (1 mL). The solvents were removedin vacuo and an additional aliquot of methanol was added to theresultant residue. Evaporation of the solvent from this mixture affordedcrude product which was purified via reverse-phase chromatography(Bondapak C18, 3×(40×100 mm), gradient of H₂O/CH₃CN (+0.1% TFA)). Theappropriate fractions were collected and lyophilized. The resultantmaterial was subsequently treated with ethanolic-hydrogen chloride,followed by evaporation and drying under vacuum to give the phenolicproduct 9 as a white tris-hydrochloride salt (0.145 g, 0.228 mmol).NMR(d₆-DMSO): δ 10.77 (br, 1H), 10.01 (br, 1H), 9.31 (br, 1H), 8.79 (d,1H), 8.67 (m, 4H), 8.37 (d, 1H), 7.97 (m, 2H), 7.81 (dt, 1H), 7.72 tm,1H), 7.52-7.36 (m, 2H), 6.57 (s, 1H), 6.22 (dd, 1H), 5.69 (d, 1H), 3.79(m, 1H), 3.68-3.30 (m, 5H), 3.04 (m, 1H), 2.92-2.68 (m, 4H), 2.33-2.10(m, 2H), 1.73-1.56 (m, 2H), 1.55-1.32 (m, 4H); MS: MH+=527 (FIG. 3).

Example 4

(2S)-2-(Acetylamino)-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthenyl]hexanamidebis-hydrochloride 10

-   Diasteromerically mixed tetralinamide lysino-sulfonamide 7 (0.195 g,    0.249 mmol) was placed into a 50 mL round-bottom flask along with a    stir bar. Acetonitrile (25 mL) was added followed by triethylamine    (0.122 mL, 0.875 mmol). With stirring, acetyl chloride (0.021 mL,    0.295 mmol) was added and the flask was flushed with argon, capped    and stirred overnight at ambient temperature. The solvents Were    removed in vacuo and the residue was taken up in methylene chloride    (75 mL). This mixture was washed with 1 N sodium hydroxide (2×25 mL)    and then with brine (1×25 mL). The organics were dried over    magnesium sulfate, filtered and concentrated in vacuo to give the    acetate product 10 as a tan solid (0.139 g, 0.233 mmol) as a 1:1    diastereomeric mixture. NMR(CDCl₃): δ 8.52 (d, 0.5H), 8.43 (d,    0.5H), 8.28 (d, 1H), 7.89 (m, 1H), 7.57 (m, 1H), 7.44 (d, 0.5H),    7.39-7.13 (m, 3.5H), 6.92 (t, 0.5H), 6.77 (d, 0.5H), 6.70-6.54 (m,    3H), 6.48 (dd, 1H), 6.34 (d, 0.5H), 5.59 (t, 0.5H), 4.40-4.06 (m,    2H), 3.78 (d, 3H), 3.29 (m, 1H), 3.19-2.82 (m, 6H), 2.01 (d, 3H),    1.92-1.71 (m, 2H), 1.72-1.32 (m, 6H); MS: MH+597 (FIG. 4).

Example 5

-   (2S)-2-(Acetylamino)-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthenyl]hexanamide    bis-hydrochloride 11-   The bis-amide 10 from the previous reaction (0.114 g, 0.191 mmol)    was placed in a 50 mL round-bottom flask along with a stir bar.    Methylene chloride (20 mL) was added and the solution was cooled on    an ice bath for several minutes. Boron tribromide in methylene    chloride (1M, 1.0 mL, 1.0 mmol) was added to the reaction mixture.    The flask was flushed with argon, capped and allowed to warm up to    ambient temperature and the mixture was stirred over 16 hours at    which time the reaction was quenched by the addition of methanol (1    mL). The solvents were removed in vacuo and the resultant material    treated with an additional aliquot of methanol. This mixture was    evaporated in vacuo to yield crude phenolic tetralinamide 11 which    was purified via reverse-phase column chromatography which allowed    for separation and purification of the racemic pairs of    diastereomers (Bondapak C18, 3×(40×100 mm), gradient of H₂O/CH₃CN    (+0.1% TFA)). After lyophilization of the appropriate fractions,    each diastereomer was treated with ethanolic-hydrogen chloride,    subjected to evaporation and lastly dried under vacuum to give the    individual racemic diastereomers as tan hydrochloride salts;    diastereomer a (0.036 g, 0.058 mmol) and diastereomer b (0.057 g,    0.092 mmol) (absolute configurations of the diastereomers were not    determined). Diastereomer a: de=100%; NMR(d₆-DMSO): δ 9.22 (v. br,    1H), 8.79 (d, 1H), 8.48 (s, 1H), 8.20 (d, 1H), 8.08-7.87 (m, 4H),    7.83-7.63 (m, 2H), 7.50-7.33 (m, 2H), 6.54 (s, 1H), 6.43-6.28 (m,    2H), 4.19(q, 1H), 3.93 (m, 1H), 3.18 (m, 1H), 3.08-2.67 (m, 6H),    1.92 (m, 1H), 1.84 (s, 3H), 1.73 (m, 1H), 1.58-1.16 (m, 6H); MS:    MH+=583. Diastereomer b: de=66%; NMR(d₆-DMSO): δ 9.20 (v. br, 1H),    8.77 (d, 1H), 8.57 (s, 1H), 8.28-8.14 (m, 2H), 8.08-7.84 (m, 3H),    7.83-7.62 (m, 2H), 7.50-7.32 (m, 2H), 6.54 (s, 1H), 6.47-6.29 (m,    2H), 4.10 (q, 1H), 3.85 (m, 1H), 3.27-3.08 (m, 2H), 3.03-2.66 (m,    5H), 1.90 (s, 3H), 1.87-1.63 (m, 2H), 1.57-1.13 (m, 6H); MS: MH+=583    (FIG. 4).

Example 6

3-[(Phenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamidebis-trifluoroacetate 17

A. Racemic 3-(N-butoxycarbonyl)aminopyrrolidine (5.13 g, 27.5 mmol) wasplaced into a 300 mL round-bottom flask along with a stir bar.Acetonitrile (100 mL) was added which gave a slurry to which was addeddiisopropylethylamine (7.2 mL, 41.3 mmol) followed by ethyl bromoacetate(3.1 mL, 28.0 mmol). The flask was flushed with nitrogen and a refluxcondenser was attached. The reaction mixture was heated at reflux for1.5 hours then allowed to cool and stir at ambient temperatureovernight. The solvents were removed in vacuo to give an oily solid.This material was taken up in methylene chloride (200 mL) and washedsuccessively with sodium bicarbonate solution (1×200mL), water (1×200mL) and brine (200 mL). The organics were dried over magnesium sulfate,filtered and the solvents removed in vacuo to give a thick oil whichslowly crystallized upon standing to give the pyrrolidinylacetate ester12 (6.96 g, 25.6 mmol). NMR(CDCl₃): δ 4.98 (br d, 1H), 4.27-4.13 (m,3H), 3.33 (s,2H), 2.98 (m, 1H), 2.83-2.66 (m, 2H), 2.48 (m, 1 H), 2.27(m, 1H), 1.67 (m, 1H), 1.44 (s, 9H), 1.28 (t, 3H).

B. Pyrrolidinylacetate ester 12 from the previous reaction (6.95 g, 25.5mmol) was put into a 300 mL round-bottom flask. A stir bar and methanol(100 mL) was added. The mixture was stirred until all of the startingmaterial had dissolved. Sodium hydroxide solution (1N, 75.0 mL, 75.0mmol) was added to the resulting solution. The reaction vessel wascapped and the mixture was allowed to stir for 20 hours at which timehydrochloric acid was added (1 N, 75.0 mL, 75.0 mmol). The resultantmixture was allowed to stir for several minutes. The solvents wereremoved in vacuo and the resulting solid was treated with methylenechloride. The organic extract was dried over magnesium sulfate, filteredand concentrated in vacuo to give pyrrolidinylacetic acid 13 as a whitepowder (6.30 g, 25.8 mmol). NMR(d₆-DMSO): δ 7.21 (br d, 1H), 4.05 (m, 1H), 3.38 (s, 2H), 3.23 (m, 1H), 3.02 (m, 2H), 2.78 (m, 1H), 2.12 (m,1H), 1.73 (m, 1H), 1.39 (s, 9H); MS: MH+=245.

C. 1,2,3,4-Tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 14 (0.331 g, 1.01 mmol), prepared from6-fluoro-β-tetralone using the chemistry described in EXAMPLE 1 (FIG.1), was placed in a 25 mL round-bottom flask along with a stir bar andDMF (5 mL) was added. The pyrrolidinylacetic acid 13 (0.250 g, 1.02mmol) from the previous reaction was added followed bydiisopropylethylamine (0.580 mL, 3.33 mmol) and then HBTU (0.387 g, 1.02mmol). The flask was flushed with argon, capped and allowed to stir atambient temperature for 2 hours. The reaction was diluted with brine (50mL) and methylene chloride (150 mL) and the layers separated. Theorganics were washed with more brine (2×50 mL). The combined aqueousbrine washes were extracted with methylene chloride (2×25 mL) and thecombined organics were dried over magnesium sulfate, filtered andconcentrated in vacuo to give the crude product. This material waspurified via reverse-phase column chromatography (Bondapak C18,3×(40×100 mm), gradient of H₂O/CH₃CN (+0.1% TFA)). Lyophilization of theappropriate fractions gave the pyrrolidineacetamide bis-TFA salt 15 as awhite powder (0.251 g, 0.35 mmol); MS: MH+=483.

D. Pyrrolidineacetamide 15 from the previous reaction (0.205 g, 0.288mmol) was placed in a 50 mL round-bottom flask along with a stir bar.Methylene chloride (25 mL) was added followed by a small amount of water(˜0.5 mL) and TFA (2 mL). The reaction was capped and allowed to stir atambient temperature for 19 hours at which time the solvents were removedin vacuo to yield 3-aminopyrrolidineacetamide tris-TFA salt 16 (0.204 g,0.282 mmol). NMR(d₆-DMSO): δ 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s, 1H),8.36 (br, 3H), 7.93 (d, 1H), 7.67 (t, 1H), 7.02 (d, 1H), 6.83 (m, 2H),4.13 (s, 2H), 4.07-3.88 (m, 3H), 3.87-3.22 (m, 4H), 3.15-2.69 (m, 4H),2.41 (m, 1H), 2.14-1.69 (m, 3H); MS: MH+=383.

E. Aminopyrrolidine acetamide 16 from the previous reaction (0.074 g,0.102 mmol) was placed into a 50 mL round-bottom flask along with a stirbar and acetonitrile (20 mL) was added. Diisopropylethylamine (0.078 mL,0.448 mmol) was added followed by benzenesulfonyl chloride (0.013 mL,0.102 mmol). The flask was flushed with argon, capped and allowed tostir at ambient temperature for 3 hours at which time the solvents wereremoved in vacuo. The residue was purified by reverse-phase columnchromatography (H₂O/CH₃CN (+0.1% TFA)). After isolation andlyophilization of the appropriate fractions,3-[(phenylsulfonyl)amino]-N-[cis- 1,2,3,4-tetrahydro-6-fluoro- 1-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamide bis-TFA salt17 was obtained as a white solid (0.067 g, 0.089 mmol). NMR(d₆-DMSO): δ8.62 (d, 2H), 8.47 (s, 1H), 8.25 (m, 1H), 7.92 (d, 1H), 7.83 (m, 2H),7.66 (m, 4H), 7.02 (d, 1H), 6.84 (m, 2H), 4.18-3.73 (m, 4H), 3.72-2.72(m, 9H), 2.07(m, 1H), 1.98-1.67 (m, 3H); MS: MH+=523 (FIG. 5).

Examples 7-8

4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-l1-piperidineacetamidebis-hydrochloride 19

4-(2,3-Dihydro-2-oxo- 1 H-benzimidazol-1-yl)-N-[trans-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamidebis-hydrochloride 20

A solution of 2-(1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU) (0.974 g, 2.57 mmol),4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidineacetic acid (1.20g, 2.57 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) inN,N-dimethylformamide (15 mL) was stirred at room temperature for 5 min.To this mixture,1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 4 (0.80 g, 2.34 mmol) was added and stirring wascontinued for 18 h. The solution was heated to 100° C. for 1 h. Thesolution was cooled and poured into a saturated solution of aqueoussodium bicarbonate. A fine green precipitate was collected byfiltration, and the solid was purified by reverse phase C₁₈ HPLC elutedwith a gradient of water/acetonitrile/trifluoroacetic acid 10/90/0.1 to90/10/0.1. The cis product 19 was isolated as a colorless solid (0.386 g22%): ¹H NMR (DMSO-d₆) δ 1.76 (m, 4 H), 2.72-3.02 (m, 4 H), 3.16 (d, 2H), 3.29-3.46 (m, 3 H), 3.54-3.75 (m, 2 H) superimposed on 3.72 (s, 3H), 3.92-4.07 (m, 3 H), 4.53-4.65 (m, 1 H), 6.63 (d, 1 H), 6.70-6.77 (m,2 H), 7.04 (br s, 3 H), 7.59 (br s, 1 H), 7.99 (t, 1 H), 8.37 (d, 1 H),8.74 (m, 2 H), 8.96 (d, 1 H), 10.5-10.71 (br s, 1 H), and 11.03 (s, 1H); MS m/e 512 (MH⁺). A mixture of cis/trans isomers ˜8/2 0.490 g (28%)was also obtained as well as the purified trans isomer 20 as a colorlesssolid (0.136 g, 8%): ¹ HNMR (DMSO-d₆) δ 1.70 (m, 6 H), 2.63-3.81 (m, 9H) superimposed on 3.72 (s, 3 H), 3.83-4.00 (m, 3 H), 4.47-4.60 m, 1 H),6.67-6.82 (m, 3 H), 7.02 (br s, 3 H), 7.21 (d, 1 H), 7.70 (t, 1 H), 8.14(d, 1 H), 8.50-8.73 (m, 3 H), 9.70-10.10 (br s,1 H), and 11.0 (s, 1 H);); MS m/e 512 (MH⁺) (FIG. 6).

Example 9

4-Acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamidebis-hydrochloride 21

1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 4 (0.75 9, 2.41 mmol) was reacted with2-(4-acetyl-4-phenyl-piperidin-1-yl)acetic acid (0.86 g, 2.65 mmol),N,N-diisopropylethylamine (2.0 mL, 11.3 mmol) and HBTU (1.01 g, 2.65mmol) in N,N-dimethylformamide (15 mL) at room temperature for 2 h asdescribed above in EXAMPLES 7-8. The product was collected by filtrationfrom the aqueous work-up. This material was dissolved in isopropanol(˜30 mL) and treated with a saturated solution of hydrochloric acid inisopropanol (˜5 mL). The solvent was evaporated in vacuo, and theresidue was triturated with diethyl ether to give4-acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamidebis-hydrochloride 21 as an amorphous pale yellow solid (1.2 g, 90%): MSm/e 482 (MH⁺) (FIG. 7).

Example 10

4-Oxo-1 -phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1,3,8-triazaspiro[4.5]decane-8-acetamidebis-hydrochloride 22

1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenaminebis-hydrochloride 4 (0.75 g, 2.41 mmol) was reacted with2-(1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one)acetic acid (1.12 g, 2.41mmol), N,N-diisopropylethylamine (1.68 mL, 9.63 mmol). mmol) and HBTU(0.91 g, 2.41 mmol) in N,N-dimethylformamide (15 mL) at room temperaturefor 4 h as described above in EXAMPLES 7-8. The product was collected byfiltration from the aqueous work up. This material was dissolved inmethanol (˜30 mL), and treated with concentrated hydrochloric acid (5mL). The solvent was evaporated in vacuo, and the residue was trituratedwith diethyl ether to give 4-oxo-1-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1,3,8-triazaspiro[4.5]decane-8-acetamidebis-hydrochloride 22 as an amorphous tan solid (1 g, 81%): 1HNMR(DMSO-d₆) 6 1.93 (s, 4 H), 2.80-3.08 (m, 4 H), 3.18-3.30 (m, 2 H),3.38-3.66 (m, 3 H), 3.70-3.89 (m, 2 H), 3.94-4.13 (m, 3 H), 4.65 (s, 2H), 6.80 (t, 2 H), 7.00-7.29 (m, 8 H), 8.03 (t, 1 H), 8.44 (d, 1 H),8.81 (br s, 2 H), 8.97 (d, 1 H), 9.16 (s, 1 H), 10.83 (br s, 1 H); MSm/e 510 (MH⁺) (FIG. 8).

Example 11

4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamidebis-hydrochloride 23

A solution of4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide19 (0.28 g, 0.37 mmol) in dichloromethane (2 mL) was added dropwise to asolution of boron tribromide (1.8 mmol) in dichloromethane (22 mL) at 0°C. After stirring the resultant solution at 0° C. for 1.5 h, methanol(˜2 mL) was added and stirring was continued at 0° C. for an additional0.5 h. The solvent was evaporated in vacuo, and the residue was purifiedby reverse phase C₁₈ HPLC using a water/acetonitrile/TFA gradient,90/10/0.1 to 10/90/0.1, as the eluant. The product was dissolved inmethanol and treated with ethanolic hydrochloric acid. The solvent wasevaporated and the process repeated twice to give4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamidebis-hydrochloride salt 23 (0.148, 68%) as a colorless solid: 1HNMR(DMSO-d6) δ 1.73-2.03 (m, 4 H), 2.70-2.94 (m, 4 H), 3.05-3.20 (br s,2 H), 3.27-3.47 (m, 3 H), 3.55-3.76 (m, 2 H), 3.92-4.15 (m, 3 H),4.54-4.67 (m, 1 H), 6.46 (d, 1 H), 6.58 (s, 2 H), 7.05 (m, s, 3 H), 7.60(br s, 1 H), 7.94 (t, 1 H), 8.30 (d, 1 H), 8.72-8.83 (m, 2 H), 8.96 (d,1 H), 9.30 (br s, 1 H), 10.64 (br s, 1 H), and 11.05 (s, 1 H); MS m/e512 (MH⁺) (FIG. 9).

Examples 12-13

trans-N-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-4-[((2-fluorophenylsulfonyl)amino)methyl]-1-cyclohexanamidehydrochloride 26

trans-N-[[[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]amino]methyl]-4-cyclohexyl]methyl]2-fluorobenzenesulfonamide bis-hydrochloride 27

A. Sodium metal (0.71 g, 30.9 mmol) was added to methanol (75 mL) andstirred at room temperature until the solid was consumed. At this time,4-fluorophenylacetonitrile (3.5 mL, 29.3 mmol) was added and the mixturewas stirred at room temperature for 10 min. 3-Pyridinecarboxaldehdye(2.77 mL, 29.3 mmol) was added and the resultant solution was heated atreflux for 2 h. The reaction was cooled to room temperature andneutralized with 2 N hydrochloric acid (16 mL, 32 mmol). The solvent wasevaporated in vacuo, and the resultant residue was partitioned betweenwater (˜200 mL) and dichloromethane (˜200 mL). The organic layer wasdried over sodium sulfate, filtered and the solvent was evaporated invacuo to give 2-(4-fluorophenyl)-3-pyridin-3-yl-acrylonitrile 24 as acolorless solid (6.11 g, 93%): ¹H NMR(CDCl₃) d 7.16 (t, 2 H), 7.42-7.47(m, 1 H), 7.48 (s, 1 H), 7.66-7.70 (m, 2 H), 8.47 (d, 1 H), 8.65 (d, 1H), 8.84 (s, 1 H); MS m/e 225 (MH⁺)

B. A suspension of 2-(4-fluoropheny)-3-pyridinyl-3-acrylonitrile 24 (1.5g, 6.68 mmol) and platinum(IV) oxide (0.51 g, 2.24 mmol) in ethanol (60mL) and water (15 mL) was reacted with hydrogen gas at a pressure of 65psi for 6 h. The catalyst was removed by filtration, and the solvent wasevaporated in vacuo. The residue was dissolved in diethyl ether (50 mL),and the small amount of insoluble material was removed by filtration.The ethereal-solution was treated with 1 N hydrogen chloride in diethylether (20 mL). A yellow solid precipitated which was collected byfiltration and washed generously with diethyl ether to giveβ-(3-pyridinylmethyl)-4-fluorophenethylamine bis hydrochloride salt 25as a pale yellow solid (1.67 g, 82%). ¹ HNMR(DMSO-d₆) δ3.03-3.21 (m, 4H), 3.44-3.53(m, 1 H), 7.13 (t, 2 H), 7.27-7.33 (m, 2 H), 7.93 (t, 1 H),8.27 (d, 1 H), 8.42 (br s, 3 H), 8.72-8.80 (m, 2 H); MS m/e 231 (MH⁺).

C. A solution of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU) (1.03 g, 2.57 mmol),trans-4-[(2-fluorophenyl)sulfonylaminomethyl]cyclohexanecarboxylic acid(1.20 g, 2.57 mmol), and N,N-diisopropylethylamine (1.9 mL, 11.1 mmol)in N,N-dimethylformamide (15 mL) was stirred at room temperature for 10min. 2-(4-Fluorophenyl)-3-pyridin-3-yl-propylamine dihydrochloride 25(0.75 g, 2.47 mmol) was added, and the resultant solution was stirred atroom temperature for 2 h. The reaction mixture was poured into water(˜100 mL) and the product was extracted into dichloromethane (˜100 mL).The organic layer was washed with water (3×100 mL), concentrated and theresultant residue purified via flash chromatography using methanol(5-10%) and triethylamine (0.5%) in dichloromethane as the eluant togive the desired cyclohexanamide as an oil. This material was dissolvedin diethyl ether (˜50 mL) and treated with 1 N hydrogen chloride indiethyl ether. A colorless solid formed which was collected byfiltration, washed with ether and dried in vacuo to giveN-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-41((2-fluorophenylsulfonyl)amino)methyl]-1-cyclohexanamidehydrochloride 26 as a colorless solid. ¹ H NMR(DMSO-d₆) δ 0.69-0.83 (m,2 H), 1.07-1.19 (m, 3 H), 1.52-1.71 (m, 4 H), 1.94 (t, 1 H), 2.66 (br s,2 H), 2.99-3.10 (m, 1 H), 3.17-3.43 (m, 4 H), 7.07 (t,.2 H), 7.16-7.21(m, 2 H), 7.35-7.47 (m, 2 H), 7.66-7.95 (m, 5 H), 8.28 (d, 1 H), and8.74 <br s, 2 H); MS m/e 528 (MH⁺) (FIG. 10).

D.N-[2-(4-Fluorophenyl)-3-(3-pyridinyl)propyl]-4-[((2-fluorophenylsulfonyl)amino)methyl]-1-cyclohexanamidehydrochloride 26 was partitioned between a saturated solution of aqueoussodium bicarbonate and dichloromethane. The organic layer was dried oversodium sulfate and the solvent was evaporated in vacuo to give the freebase as an oil. This oil (0.5 g, 0.944 mmol) was dissolved intetrahydrofuran (20 mL), and the resultant solution was added dropwiseto a solution of borane (4.0 mmol) in tetrahydrofuran (14 mL) at ambienttemperature. The solution was heated at reflux for 2 h. The resultantmixture was cooled to room temperature and several drops of water wereadded until unreacted borane was consumed. A 4 N solution ofhydrochloric acid (2 mL) was added and the solution heated at reflux for45 min. After the solution had cooled, 3 N aqueous sodium hydroxide wasadded (2.7 mL), and the mixture was concentrated in vacuo. The residuewas partitioned between water (˜50 mL) and dichloromethane (˜50 mL). Theorganic layer was dried over sodium sulfate, and the solvent wasevaporated in vacuo. The residue was dissolved in diethyl ether (˜20 mL)and treated with 1 N hydrogen chloride in diethyl ether (˜4 mL). Thecolorless precipitate was collected by filtration, washed generouslywith diethyl ether and dried in vacuo to givetrans-N-[[[2-(4-fluorophenyl)-3q3-pyridinyl)propyl]amino]methyl]-4-cyclohexyl]methyl]2-fluorobenzenesulfonamide bis-hydrochloride 27 (0.371 g, 67%): ¹HNMR(DMSO-d₆) δ 0.70-0.87 (m, 4 H), 1.22-1.36 (br s, 1 H), 1.64-1.88 (m,6 H), 2.65-2.77 (m, 3 H), 2.99-3.33 (m, 3 H), 3.54-3.70 (m, 2 H), 7.13(t, 2 H), 7.24 -7.34 (m, 2 H), 7.37-7.48 (m, 2 H), 7.67-7.87 (m, 3 H),7.96 (t, 1 H), 8.17 (d, 1 H), 8.68 (s, 1 H), 8.70 (s, 1 H), 9.03 (br s,1 H), and 9.24<br s, 1 H); MS m/e 514 (MH⁺) (FIG. 10).

Example 14

N-[2-(4-Fluorophenyl)-3-(3-pyridinyl)propyl]-4-1[2-fluorophenylsulfonyl)amino]-1-piperidineacetamidebis-trifluoroacetate 30.

A. A solution of[4-(1,1-dimethylethoxy)carbonylamino-piperidin-1-yl]acetic acid (0.5 g,1.94 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.73 g, 1.94 mmol), and N,N-diisopropylethylamine(1.5 mL, 8.71 mmol) in N,N-dimethylformamide (15 mL) was stirred at roomtemperature for 5 min. P-(3-Pyridinylmethyl)-4-fluorophenethylaminedihydrochloride 25 (0.586 g, 1.94 mmol) was added, and the resultantsolution was stirred at room temperature for 24 h. The solution waspoured into a saturated solution of aqueous sodium bicarbonate (˜100 mL)and the product was extracted into dichloromethane (˜100 mL). Theorganic layer was washed with water (5×˜100 mL) and dried over sodiumsulfate. The solvent was evaporated in vacuo to give thepiperidineacetamide 28 as an oil, 0.52 g (57%):

¹H NMR(CDC;₃) δ 0.98-1.25 (m, 2 H), 1.45 (s, 9 H), 1.71-1.79 (m, 2 H),2.05-2.17 (m, 2 H), 2.41-2.50 (m, 2 H), 2.75-3.00 (m, 3 H), 3.04-3.17(m, 1 H), 3.33-3.47 (m, 2 H), 3.72-3.83 (m, 1 H), 4.36 (br s,1 H),6.93-7.14 (m, 7 H), 7.25 (m, 1 H), 8.24 (s,1 H), 8.39 (d, 1 H); MS m/e471 (MH⁺).

B. A solution of the piperidineacetamide 28 (0.46 g, 0.977 mmol) indichloromethane (6 mL) was treated with trifluoroacetic acid (2 mL) andstirred at room temperature for 3 h. The solvent was evaporated invacuo. The residue was dissolved in 1,2-dichloroethane (10 mL), and thesolvent evaporated in vacuo (repeated twice to remove residualtrifluoroacetic acid), to give the 4-amino-1-piperidineacetamide 29 as atris-trifluoroacetate salt, isolated as an amber glass, 0.66 g (95%): ¹HNMR(DMSO-d₆); MS m/e 371 (MH⁺).

C. 2-Fluorobenzenesulfonyl chloride (25 mg, ).126 mmol) was added to asolution of the 4-amino-1-piperidineacetamide 29 (82 mg, 0.115 mmol) andN,N-diisopropylethylamine (0.10 mL, 0.575 mmol) in acetonitrile (1 mL)at room temperature. The mixture was stirred at room temperature for 16h and then water (0.30 mL) was added and the solution was applied to aC₁₈ reverse phase column for purification by HPLC. The column was elutedwith a gradient of water/acetonitrile/trifluoroacetic acid to giveN-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-4-[(2-fluorophenylsulfonyl)amino]-1-piperidineacetamidebis-trifluoroacetate 30 as a colorless solid, 28 mg (32%): ¹HNMR(DMSO-d₆) δ 1.70-1.85 (m, 4 H), 2.91-3.47 (m, 10 H), 3.66-3.80 (m, 2H), 7:07 (t, 2 H), 7.18 (m, 2 H), 7.38-7.50 (m, 2 H), 7.64 (t, 1 H),7.71-7.85 (m, 2 H), 7.92,(d, 1 H), 8.31 (d, 1 H), 8.49 (s, 1 H), 8.57(s, 1 H), 8.60 (s, 1 H); MS m/e 529 (MH⁺) (FIG. 11).

Additional compounds of this invention that were prepared using theexperimental protocols described above include: Mass Spectral Data ofCompounds A

Calc # R₁ R₂ m B₁ B₂ Y L Z MH+ M 31 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

496 495 19 6-OMe 3-pyridyl 1 —CH₂— —CH₂— C═O

526 525 20 6-OMe 3-pyridyl (trans) 1 —CH₂— —CH₂— C═O

526 525 23 6-OH 3-pyridyl 1 —CH₂— —CH₂— C═O

512 511 32 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

525 524 33 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

507 506 34a (H) 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

507 506 34b (H) 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

507 506 35 6-OMe 3-pyridyl 1 —CH₂— —CH₂— C═O

555 554 7a 6-OMe 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

555 554 7b 6-OMe 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

555 554 8a 6-OMe 3-pyridyl (diast-A) 1 —CH₂— —CH₂— —CH₂—

541 540 9a 6-OH 3-pyridyl (diast-A) 1 —CH₂— —CH₂— —CH₂—

527 526 36 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

567 566 37 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

549 548 38a (H) 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

549 548 38b (H) 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

549 548 10 6-OMe 3-pyridyl 1 —CH₂— —CH₂— C═O

597 596 39 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

611 610 40 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

578 577 41 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

550 549 42 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

549 548 43a (H) 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

535 534 43b (H) 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

535 534 11a 6-OH 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

583 582 11b 6-OH 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

583 582 17 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

523 522 44 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

501 500 45 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

516 515 46 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

517 516 47 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

515 514 48 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

537 536 49 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

555 554 22 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

510 509 21 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

482 481 50 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

537 536 51 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

498 497 52 6-OMe 3-thienyl 1 —CH₂— —CH₂— C═O

572 571 53 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

496 495 54 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

497 496 55 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

483 482 56 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

483 482 57 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

486 482 58 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

523 522 59 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

523 522 60 6-F 3-pyridyl 1 —CH₂— —CH₂— C═O

487 486 61 6-OMe 3-thienyl 1 —CH₂— —CH₂— C═O

531 530 62 6-OMe 3-thienyl 1 —CH₂— —CH₂— —CH₂—

517 516 63 6-OMe 3-thienyl 1 —CH₂— —CH₂— C═O

560 559 64 6-OMe 3-thienyl 1 —CH₂— —CH₂— —CH₂—

546 545 65 (H) 3-pyridyl 1 —CH₂— —CH₂— —CH₂—

493 492 66 (H) 3-pyridyl (diast-A) 1 —CH₂— —CH₂— —CH₂—

493 492 67 6-F 3-pyridyl (diast-A) 1 —CH₂— —CH₂— —CH₂—

529 528 68 (H) 3-pyridyl 1 —CH₂— —CH₂— —CH₂—

521 520 69 6-OMe 5(4)- imidazolyl 1 —CH₂— —CH₂— —CH₂—

530 529 70 6-F 3-pyridyl (diast-A) 1 —CH₂— —CH₂— C═O

543 542 71 6-F 3-pyridyl (diast-B) 1 —CH₂— —CH₂— C═O

543 542 72 (H) 3-pyridyl 1 —CH₂— —CH₂— C═O

626 625 73 6-OMe 5(4)- imidazolyl 1 —CH₂— —CH₂— C═O

515 514 74 6-OMe 3-thienyl 1 —CH₂— —CH₂— C═O

602 601 75 6-OMe 4-Cl- phenyl 1 —CH₂— —CH₂— C═O

588 587 76 6-OMe 4-Cl- phenyl 1 —CH₂— —CH₂— —CH₂—

574 573 77 6-F vinyl 1 —CH₂— —CH₂— C═O

474 473 78 6-F vinyl 1 —CH₂— —CH₂— —CH₂—

460 459 79 6-OMe vinyl 1 —CH₂— —CH₂— C═O

475 474 80 6-OMe vinyl 1 —CH₂— —CH₂— —CH₂—

461 460 81 6-OH vinyl 1 —CH₂— —CH₂— —CH₂—

447 446 82 6-OMe (H) 0 —CH₂— —CH₂— CH═O

435 434 83 6-OH (H) 0 —CH₂— —CH₂— CH═O

421 420 84 6-OMe (H) 0 —CH₂— —CH₂— —CH₂—

461 460 85 6-OH (H) 0 —CH₂— —CH₂— —CH₂—

447 446 86 6-OMe 3-pyridyl 1 H H CH═O

500 499 87 6-OH 3-pyridyl 1 H H CH═O

486 485 88 6-OMe 3-pyridyl 1 H H CH═O

540 539 89 6-OMe 3-pyridyl 1 H H —CH₂—

526 525 90 6-OH 3-pyridyl 1 H H CH═O

526 525 91 6-OH 3-pyridyl 1 H H —CH₂—

512 511 26 6-F 3-pyridyl 1 H H CH═O

528 527 27 6-F 3-pyridyl 1 H H —CH₂—

514 513 92 6-F 3-pyridyl 1 H H CH═O

475 474 30 6-F 3-pyridyl 1 H H CH═O

529 528 93 (H) 3-pyridyl 1 —CH₂— —CH₂— CH═O

471 470 94 6-OMe (H) 0 H H CH═O

449 448 95 6-OMe (H) 0 H H —CH₂—

435 434 96 6-OH (H) 0 H H —CH₂—

421 420In Vitro Assays

NPY5 HTS Centrifugation Assay

The compounds described in this invention were evaluated for binding tothe human neuropeptide Y5 receptor.

Stable Transfection

The human NPY5 receptor cDNA (Genbank Accession number U66275) wasinserted into the vector pCIneo (Invitrogen) and transfected into humanembryonic kidney cells (HEK-293) via Calcium phosphate method (Cullen1987). Stably transfected cells were selected with G-418 (600 ug/mL).Stably transfected cells served as the source for the membranes for theNPY5 receptor binding assay.

Membrane Preparation

NPY5-transfected HEK293 cells were grown to confluence in 150 cm²culture dishes. Cells were washed once with phosphate-buffered saline(Gibco Cat# 14040-133). Cells were then incubated in phosphate-bufferedsaline without Calcium and without Magnesium, supplemented with 2 mMEDTA. Cells were incubated for 10 minutes at room temperature and thecells were collected by repetitive pipeting. Cells were formed intopellets and then frozen at −80 until needed. Frozen pellets werehomogenized with a polytron at full speed for 12 seconds in ahomogenization buffer (20 mM Tris HCl, 5 mM EDTA, pH 7.4). Homogenateswere centrifuged for 5 minutes at 4C at 200g. Supernatants weretransferred to corex tubes and centrifuged for 25 minutes at 28,000 g.Pellets were re-suspended in Binding (20 mM HEPES, 10 mM NaCl, 0.22 mMKH₂PO₄, 1.3mM CaCl₂, 0.8 mM MgSO₄, pH 7.4). Membranes were kept on iceuntil use.

A competition binding assay, known to those skilled in the art, was usedin which compounds of formula A compete with ¹²⁵I-PYY for binding tocell membranes. In simple terms, the less ¹²⁵I-PYY bound to themembranes implies that a compound is a good inhibitor (competitor).Bound ¹²⁵I-PYY is determined by centrifugation of membranes, aspiratingsupernatant, washing away residual ¹²⁵I-PYY and subsequently countingthe bound sample in a g-counter.

Procedure for Radioligand Binding Assay

Compounds to be tested were prepared as 10× stocks in binding buffer andadded first to assay tubes (RIA vials, Sarstedt). Twenty (20) μL of each10× compound stock is pipeted into vials and 80 μL of ¹²⁵I-PYY (NENcatalog number NEX240), which has been diluted to a concentration of 200pM in 0.25% BSA in binding buffer, is added to the compound tubes (finalconcentration of ¹²⁵I-PYY is 80 pM). To each tube is added 100 μL ofmembranes and the mixture is agitated by pipeting 2 times. Samples areincubated for 1 hr at room temperature. Aluminum cast plates (Sarstedt)containing the vials are then centrifuged 10 minutes at 3200 rpm in aSorvall RT6000. Supernatant is then aspirated. To each vial 400 μL PBSis added and this is then aspirated again. Vials are then put in carrierpolypropylene 12×75 tube and counted in gamma counter (Packard).Non-specific binding is determined in the presence of 300 nM NPY.Percent inhibition of ¹²⁵I-PYY binding is calculated by subtractingnon-specific binding from the test samples (compound (I)), taking thesecounts and dividing by total binding, and multiplying by 100. Inhibitoryconcentration values (IC₅₀) of compounds that show appreciableinhibition of ¹²⁵I-PYY binding are calculated by obtaining percentinhibition of 125l-PYY binding values at different concentrations of thetest compound, and using a graphing program such as GraphPad Prism (SanDiego, Calif.) to calculate the concentration of test compound thatinhibits fifty-percent of ¹²⁵I-PYY binding (Table 4). These operationsare known to those skilled in the art. TABLE 2 Binding Affinities ofCompounds A for the Human NPY Y5 Receptor (expressed as % Inhibition of¹²⁵I-PYY Binding) A

% Inh % Inh # @ 3 uM @ 300 nM 7a 97 69 7b 67 11 8 100 96 9 98 104 10 9660 17 102 98 19 101 69 20 96 88 21 98 83 22 70 32 23 100 96 26 110 10827 110 105 30 110 100 31 100 91 32 100 62 33 96 52 34a 97 87 34b 99 6135 96 54 36 95 22 37 102 89 38a 104 80 38b 101 89 39 95 70 40 92 21 4194 54 42 85 21 43a 93 84 43b 86 62 44 98 93 45 95 68 46 107 90 47 98 9148 103 97 49 95 85 50 108 103 51 102 85 52 100 96 53 92 84 54 100 99 55106 96 56 94 88 57 93 87 58 91 93 59 93 90 60 109 86 61 87 66 62 103 7463 71 33 64 103 91 65 98 79 66 102 98 67 99 102 68 108 109 69 56 26 7092 93 71 73 59 72 73 41 73 63 32 74 100 89 75 78 28 76 91 45 77 84 56 7875 65 79 99 69 80 82 47 81 94 89 82 85 63 83 92 72 84 93 79 85 100 96 8691 88 87 96 97 88 103 104 89 100 103 90 88 93 91 100 104 92 104 92 93 9781 94 98 93 95 102 96 96 98 91In Vivo Assays

Rodent Feeding Model: Measurement of Food Intake in Food-Deprived Rats

Male Long-Evans rats (180-200 grams) are housed individually and aremaintained on a once-a-day feeding schedule (i.e.10 a.m. until 4 p.m.)for five days following quarantine to allow the animals to acclimate tofeeding on powdered chow (#5002 PMI Certified Rodent Meal) during theallotted time. The chow is made available in an open jar, anchored inthe cage by a wire, with a metal follower covering the food to minimizespillage. Water is available ad-libitum.

Animals are fasted for 18 hours prior to testing. At the end of thefasting period, animals are administered either compounds of theinvention or vehicle. Vehicle and test compounds are administered eitherorally (5 mL/kg) 60 minutes prior to the experiment, or 30 minutes priorwhen given subcutaneously (1 mL/kg) or intraperitoneally (1 mL/kg).Compounds of the invention are administered orally as a suspension inaqueous 0.5% methylcellulose-0.4% Tween 80, or intraperitoneally as asolution or suspension in PEG 200; compound concentrations typicallyrange from 1 mg/kg to 100 mg/kg, preferably from 10-30 mg/kg. Foodintake is measured at 2, 4, and 6 hours after administration by weighingthe special jar containing the food before the experiment and at thespecified times. Upon completion of the experiment, all animals aregiven a one-week washout period before retesting.

Percent reduction of food consumption is calculated subtracting thegrams of food consumed by the treated group from the grams of foodconsumed by the control group divided by the grams of food consumed bythe control group, multiplied by 100.${\%\quad{change}} = {\frac{{Treatment} - {Vehicle}}{Vehicle} \times 100}$

A negative value indicates a reduction in food consumption and apositive value indicates an increase in food consumption. FoodConsumption (grams) Dose (mg/kg) 2 hrs 4 hrs 6 hrs 2-6 hrs Compound(#rats) (% chg.) (% chg.) (% chg.) (% chg.) Vehicle N = 6 8.85 g 13.97g  22.85 g  14.00 g  70 30 (i.p.) 1.30 g 3.44 g 6.14 g 4.84 g N = 7(−85.3%) (−75.4%) (−73.1%) (−65.4%)

1-9. (canceled)
 10. A compound of claim 17 selected from the groupconsisting of:


11. A compound of claim 17 selected from the group consisting of:


12. (canceled)
 13. A compound of claim 17 which is:3-[(Phenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamidebis-trifluoroacetate. 14-16. (canceled)
 17. A compound of the formula

wherein R₁ is independently selected from the group consisting of H;alkyl; substituted alkyl; alkoxy; halo; substituted alkoxy; hydroxy;trifluoralkyl; nitro; amino; alkylamino; cycloalkylamino; cyano;carboxy; cycloalkyl; phenyl; and substituted phenyl; R₂ is pyridyl; B₁is hydrogen; B₂ is hydrogen; or B₁ and/or B₂ are methylene and joinedtogether to form a five or six membered ring; Y is methylene orcarbonyl; L is (N-methylene)pyrrolidin-3-yl;

Z is selected from the group consisting of aryl;

N-sulfonamido;

N-(aryl)sulfonamido;

arylamido;

arylureido;

arylacetamido:

(aryloxy)carbonylamino;

2,3-dihydro-2-oxo-1H-benzimidazol-1-yl;

and 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl;

R₃ is independently selected from the group consisting of C₁₋₆ alkyl;substituted C₁₋₈alkyl; cycloalkyl; substituted cycloalkyl; naphthyl;substituted naphthyl; heteroaryl; and substituted heteroaryl; R₄ isindependently selected from the group consisting of hydrogen; C₁₋₈alkyl;C₁₋₈alkoxy; substitued C₁₋₈alkoxy; hydroxy; halogen; cyano; nitro;amino; C₁₋₈alkylamino; and C₁₋₈dialkylamino; R₅ is independentlyselected from the group consisting of hydrogen; C₁₋₈alkyl;C₁₋₈alkylcarbonyl; aroyl; carbamoyl; amidino; C₁₋₈alkyl;C₁₋₈alkylaminocarbonyl; (arylamino)carbonyl; and arylC₁₋₈ alkylcarbonyl;R₆ is independently selected from hydrogen and C₁₋₈alkyl; n is 1-2; m is0-3; p is 1-3; and q is 1-3; provided that when L is(N-methylene)piperazin-4-yl, then Z is phenyl or naphthyl; when L is(N-methylene)piperidin-4-yl, then Z is N-sulfonamido,N(aryl)sulfonamido, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, benzamido,phenylureido, phenylacetamido or (phenoxy)carbonylamino; when L is(N-methylene)-4-acetyl- piperidin-4-yl, then Z is phenyl or naphthyl andY is carbonyl; and when L is (N-methylene)piperidin-4,4-diyl, then Z is1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl and Y is carbonyl; andenantiomers, diastereomers and pharamaceutically acceptable saltsthereof.
 18. A method of treating disorders and diseases associated withNPY receptor subtype 5 selected from the group consisting of eatingdisorders, obesity, diabetes, memory loss, epileptic seizures, migraine,sleep disturbances, pain, sexual.reproductive disorders, depression andanxiety comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim
 17. 19. Apharmaceutical composition for the treatment of diseases or disordersassociated with the NPY Y5 receptor subtype selected from the groupconsisting of eating disorders, obesity, diabetes, memory loss,epileptic seizures, migraine, sleep disturbances, pain,sexual.reproductive disorders, depression and anxiety comprising atherapeutically effective amount of a compound of claim 17 and apharmaceutically acceptable carrier